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Glucarpidase is a carboxypeptidase enzyme used to reduce plasma concentrations of methotrexate in patients with impaired renal function.
Glucarpidase is a carboxypeptidase enzyme used to reduce plasma concentrations of methotrexate in patients with impaired renal function.
Methotrexate is an anticancer agent widely used to treat various cancers: it is often used in higher doses in leukemias and lymphomas. As methotrexate and its metabolites are primarily excreted in the kidneys, patients with reduced renal function are at an elevated risk for increased drug exposure and methotrexate toxicity. Methotrexate itself can cause renal toxicity at high doses: methotrexate-induced renal damage can occur by precipitation of methotrexate and its breakdown products in the renal tubules, or from a direct toxic effect of the drug. Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. Glucarpidase converts methotrexate to its inactive metabolites glutamate and 2,4-diamino-N-methylpteroic acid (DAMPA), which is a nontoxic metabolite. DAMPA is later excreted in urine or further metabolized by the liver into hydroxyl-DAMPA, DAMPA-glucuronide, and hydroxy-DAMPA-glucuronide. Glucarpidase provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.
Glucarpidase is indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per litre) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function. In the European prescribing information, glucarpidase is specified for use in adults and children aged 28 days and older. Glucarpidase is not recommended for use in patients who exhibit the expected clearance and expected plasma methotrexate concentration. Reducing plasma methotrexate concentration in these patients may result in subtherapeutic exposure to methotrexate.
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